Abstract Cytotoxic CD8+ T lymphocytes are the major effector cells of immune system that kill virally infected and cancerous cells. We recently discovered a novel role of interleukin-17A (IL-17A) in promoting cytotoxicity of CD8+ T cells in a mouse model of West Nile virus (WNV) infection. Specifically, we found that 1) cytotoxicity of CD8+ T cells isolated from WNV-infected IL-17A deficient (Il17a-/-) mice is much lower than those from wild- type control mice, resulting in increased viral burden in the brain and higher death rate of Il17a-/- mice; and 2) injection of recombinant mouse IL-17A (rIL-17A) into wild-type mice as late as on day 6 post WNV infection increases the expression of the CD8+ T cell cytotoxic mediator genes (perforin, granzyme and fas-l), which profoundly reduces the viral burden in the brain and increases the survival, suggesting a therapeutic role of IL- 17A in treating WNV infection. In addition, our recent RNA sequencing (RNA-seq) results indicate that IL- 17A may facilitate CD8+ T cell effector functions through activating mammalian target of rapamycin (mTOR) kinase signaling pathway. In this proposal, we will address two key questions: 1) does IL-17A signaling directly act on CD8+ T cells in promoting their cytotoxicity during WNV infection? and 2) what are the key molecular and cellular mechanisms by which IL-17A enhances CD8+ T cell cytotoxicity? Addressing these questions will expand our current knowledge of biological functions of IL-17A and CD8+ T cells, and may also open new opportunities for the development of therapeutic strategies against WNV infection, other viral infections, and even cancer by enhancing IL-17A-mediated CD8+ T cell cytotoxicity.